Dendritic cells (DCs) and T cells are among the first leukocytes targeted by HIV after mucosal exposure and DCs promote virus replication in concert with CD4+ T cells. Different subsets of DCs and T cells, and the type of virus influence the level of virus growth in the DC-T cell milieu. DCs express CD4, chernokine receptors (CCRs), and mannose-dependent C-type lectin receptors (MCLRs) that are used by the virus for binding and entry. With such diversity, DCs promote virus amplification in two ways; replicating virus themselves and transmitting this to permissive CD4+ T cells (immature DCs) or directly transferring entrapped virions to CD4+ T cells in the absence of DC infection (immature and mature DCs). Directly interfering with specific DC-virus interactions and transmission of virus between cells represents a promising anti-viral strategy that is of relevance to the development of mechanism-based microbicides. This project will focus on defining how putative attachment, fusion, and entry (AFE) inhibitory that target virus envelope interactions with CD4, MCLRs, or CCRs impact DC-virus interplay and their ability to drive virus spread between cells in vitro, and whether the presence of common co-pathogens like HSV-2 or Candida albicans impact the efficacy of the AFE inhibitors. The questions being considered are: 1 - Which AFE inhibitors block binding, uptake, or spread of virus by DCs in the DC-T cell milieu without interfering with normal DC biology? 2 - Are AFE inhibitors able to impede virus dissemination to antigen-specific T cells? 3 - Do mucosal co-pathogens impact how AFE inhibitors block HIV capture and spread by DCs? These studies will reveal critical details about how agents that prevent virus fusion and entry block DC-driven virus spread, a central event in establishing mucosal infection. Identifying effective strategies to impede DC-virus interplay without impairing DC function even in the face of co-pathogens is vital to advance the microbicide field.